Patients With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Metastatic Colorectal Cancer
Interventions:	Drug: Regorafenib (Stivarga, BAY73-4506) Drug: Placebo

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
Regorafenib (Stivarga, BAY73-4506)	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Placebo	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle

Participant Flow: Overall Study

	Regorafenib (Stivarga, BAY73-4506)	Placebo
STARTED	505	255
Participants Received Treatment	500	253
COMPLETED	386	232
NOT COMPLETED	119	23
Adverse Event	42	7
Withdrawal by Subject	16	5
Protocol Violation	2	0
Physician Decision	2	0
ongoing with treatment	52	9
did not receive study treatment	5	2

Baseline Characteristics

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Outcome Measures

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1. Primary:

Overall Survival [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis (IA). ]

Measure Type	Primary
Measure Title	Overall Survival
Measure Description	Overall survival (OS) was defined as the time (days) from randomization to death due to any cause. Patients alive at the time of analysis were censored at the last date known to be alive. If a patient was lost to follow-up and there was no contact after randomization, this patient was censored at Day 1.
Time Frame	From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis (IA).
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to treat (ITT)

Reporting Groups

	Description
Regorafenib (Stivarga, BAY73-4506)	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Placebo	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle

Measured Values

	Regorafenib (Stivarga, BAY73-4506)	Placebo
Number of Participants Analyzed [units: participants]	505	255
Overall Survival [units: Days] Median ( 95% Confidence Interval )	196 ( 178 to 222 )	151 ( 134 to 177 )

Statistical Analysis 1 for Overall Survival

Groups ^[1]	All groups
Method ^[2]	Log Rank
P Value ^[3]	0.005178
Hazard Ratio (HR) ^[4]	0.774
95% Confidence Interval	( 0.636 to 0.942 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Sample size based on primary efficacy endpoint of OS. The study was designed to have 90% power to detect 33.3% increase in median OS (i.e. hazard ratio of 0.75, Regorafenib / Placebo). Assuming 1-sided overall alpha of 0.025, randomization ratio of 2:1 for Regorafenib and Placebo, and 2 formal interim analyses of OS using an O’Brien-Fleming-type error spending function, a total of 582 death events were required for primary completion. Results based on 2nd planned formal IA with 432 total events.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	According to protocol specified O'Brien-Fleming type alpha spending function and 432 death events at 2nd IA, the pre-specified alpha (false positive rate) for this analysis was 0.009279 (1-sided).
[4]	Other relevant estimation information:
	Two treatment groups compared using a stratified log-rank test, stratified by same stratification factors as randomization. Hazard ratio (Regorafenib / Placebo) and its 95% confidence interval calculated using Cox model, stratified by same factors.

2. Secondary:

Progression-free Survival (Based on Investigator’s Assessment) [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]

Measure Type	Secondary
Measure Title	Progression-free Survival (Based on Investigator’s Assessment)
Measure Description	Progression-free survival was defined as the time (days) from date of randomization to date of first observed disease progression (radiological or clinical) or death due to any cause, if death occurred before progression was documented.
Time Frame	From randomization of the first subject until the database cut-off approximately 14 months later (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT

Reporting Groups

	Description
Regorafenib (Stivarga, BAY73-4506)	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Placebo	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle

Measured Values

	Regorafenib (Stivarga, BAY73-4506)	Placebo
Number of Participants Analyzed [units: participants]	505	255
Progression-free Survival (Based on Investigator’s Assessment) [units: Days] Median ( 95% Confidence Interval )	59 ( 57 to 65 )	52 ( 51 to 53 )

Statistical Analysis 1 for Progression-free Survival (Based on Investigator’s Assessment)

Groups ^[1]	All groups
Method ^[2]	Log Rank
P Value ^[3]	<0.000001
Hazard Ratio (HR) ^[4]	0.494
95% Confidence Interval	( 0.419 to 0.582 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Two treatment groups compared using a stratified log-rank test, stratified by same stratification factors as randomization. Hazard ratio (Regorafenib / Placebo) and its 95% confidence interval calculated using Cox model, stratified by same factors.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Comparison based on pre-specified alpha level of 0.025 (1-sided).
[4]	Other relevant estimation information:
	Hazard ratio (Regorafenib / Placebo)

3. Secondary:

Objective Tumor Response [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]

Measure Type	Secondary
Measure Title	Objective Tumor Response
Measure Description	The objective tumor response was defined as the percentage of patients with complete response (CR, tumor disappears) or partial response (PR, sum of lesion sizes decreased at least 30% from baseline) as best overall response. A best overall response was defined for all patients, using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1. Patients whose best overall response was not CR or PR, and any patients with no post-baseline assessments were considered nonresponders for the analysis.
Time Frame	From randomization of the first subject until the database cut-off approximately 14 months later (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT

Reporting Groups

	Description
Regorafenib (Stivarga, BAY73-4506)	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Placebo	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle

Measured Values

	Regorafenib (Stivarga, BAY73-4506)	Placebo
Number of Participants Analyzed [units: participants]	505	255
Objective Tumor Response [units: Percentage of participants]	1.0	0.4

Statistical Analysis 1 for Objective Tumor Response

Groups ^[1]	All groups
Method ^[2]	Cochran-Mantel-Haenszel
P Value ^[3]	0.188432
Difference ^[4]	-0.60
95% Confidence Interval	( -1.74 to 0.53 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Two treatment groups compared using Cochran-Mantel-Haenszel (CMH) test adjusting for same stratification factors as at randomization.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Comparison based on pre-specified alpha level of 0.025 (1-sided).
[4]	Other relevant estimation information:
	Difference = Placebo - Regorafenib 160 mg

4. Secondary:

Disease Control [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]

Measure Type	Secondary
Measure Title	Disease Control
Measure Description	Disease control was defined as the percentage of patients whose best response was not PD [sum of lesion sizes increased at least 20% from smallest sum on study or new lesions] (ie, CR [tumor disappears], PR [sum of lesion sizes decreased at least 30% from baseline] or SD (stable disease)). SD included if at least 6 weeks after randomization.
Time Frame	From randomization of the first subject until the database cut-off approximately 14 months later (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT

Reporting Groups

	Description
Regorafenib (Stivarga, BAY73-4506)	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Placebo	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle

Measured Values

	Regorafenib (Stivarga, BAY73-4506)	Placebo
Number of Participants Analyzed [units: participants]	505	255
Disease Control [units: Percentage of participants]	41.0	14.9

Statistical Analysis 1 for Disease Control

Groups ^[1]	All groups
Method ^[2]	Cochran-Mantel-Haenszel
P Value ^[3]	<0.000001
Difference ^[4]	-25.94
95% Confidence Interval	( -32.06 to -19.82 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Two treatment groups compared using Cochran-Mantel-Haenszel (CMH) test adjusting for same stratification factors as at randomization.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Comparison based on pre-specified alpha level of 0.025 (1-sided).
[4]	Other relevant estimation information:
	Difference = Placebo - Regorafenib 160 mg

5. Secondary:

Tumor Response [ Time Frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. ]

Measure Type	Secondary
Measure Title	Tumor Response
Measure Description	A tumor response (best overall response) was defined for all patients, using the RECIST criteria, version 1.1. Categories: complete response (CR, tumor disappears), partial response (PR, sum of lesion sizes decreased at least 30% from baseline), stable disease (SD, steady state of disease), progressive disease (PD, sum of lesion sizes increased at least 20% from smallest sum on study or new lesions). Clinical PD considered when radiographic imaging not possible.
Time Frame	From randomization of the first subject until the database cut-off approximately 14 months later (19May2012 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT

Reporting Groups

	Description
Regorafenib (Stivarga, BAY73-4506)	Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle
Placebo	Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle

Measured Values

	Regorafenib (Stivarga, BAY73-4506)	Placebo
Number of Participants Analyzed [units: participants]	505	255
Tumor Response [units: Percentage of participants]
Complete Response (CR)	0	0
Partial Response (PR)	1.0	0.4
Stable Disease (SD)	42.8	14.5
Progressive Disease (PD)	49.5	80.0
Non CR/Non PD	0.8	0.4
Not applicable	0.2	0
Not assessed	5.7	4.7

No statistical analysis provided for Tumor Response

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: The agreed point of publication is 12-18 months after database lock at the earliest. Bayer will have 30-45 days to review publications, and may request an additional publication delay of up to 60 days to allow for filing a Patent Application (if applicable). No publication of single center data should be done prior of publication if multi-center data.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
At 2nd IA, pre-specified O’Brien-Fleming-type efficacy boundary was crossed. DMC concluded OS result positive and after positive risk benefit assessment, recommended unblinding of study. OS from 2nd IA are the final formal and definitive results.

Results Point of Contact:

Name/Title: Therapeutic Area Head
Organization: BAYER
e-mail: clinical-trials-contact@bayerhealthcare.com

No publications provided by Bayer

Publications automatically indexed to this study:

Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouché O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. doi: 10.1016/S0140-6736(12)61900-X. Epub 2012 Nov 22.

Mross K, Frost A, Steinbild S, Hedbom S, Büchert M, Fasol U, Unger C, Krätzschmar J, Heinig R, Boix O, Christensen O. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res. 2012 May 1;18(9):2658-67. Epub 2012 Mar 15.

Responsible Party:	Therapeutic Area Head, Bayer HealthCare Pharmaceuticals Inc.
ClinicalTrials.gov Identifier:	NCT01103323 History of Changes
Other Study ID Numbers:	14387, 2009-012787-14
Study First Received:	April 8, 2010
Results First Received:	October 19, 2012
Last Updated:	April 12, 2013
Health Authority:	Germany: Federal Institute for Drugs and Medical Devices France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis) Italy: National Institute of Health United Kingdom: Medicines and Healthcare Products Regulatory Agency Czech Republic: State Institute for Drug Control Hungary: National Institute of Pharmacy Australia: Department of Health and Ageing Therapeutic Goods Administration China: Food and Drug Administration Japan: Pharmaceuticals and Medical Devices Agency Brazil: National Health Surveillance Agency Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica Switzerland: Swissmedic Canada: Health Canada Spain: Spanish Agency of Medicines Portugal: National Pharmacy and Medicines Institute Turkey: Ministry of Health Israel: Ministry of Health Netherlands: The Central Committee on Research Involving Human Subjects (CCMO) Belgium: Federal Agency for Medicinal Products and Health Products United States: Food and Drug Administration